Bone is in a constant state of flux, being built up by bone-forming cells called osteoblasts while also being broken down or resorbed by cells known as osteoclasts. Osteoblasts arise from osteoprogenitor cells located in the deeper layer of periosteum and the bone marrow. Osteoprogenitors are immature progenitor cells that express the master regulatory transcription factor Cbfa1/Runx2. Osteoprogenitors are induced to differentiate under the influence of growth factors. Once osteoprogenitors start to differentiate into osteoblasts, they begin to express a range of genetic markers including Osterix.
During childhood and adolescence, bone formation is dominant; bone length and width increase with age, ending at early adulthood when peak bone mass is attained. At some age, the rate of bone resorption in humans starts to exceed the rate of bone formation. Women experience additionally accelerated bone loss after menopause, when the estrogen level decreases.
Osteoporosis is a progressive bone disease that is characterized by a decrease in bone mass and density and that leads to an increased risk of fracture. Osteoporosis occurs primarily as a result of normal aging, but can arise as a result of impaired development of peak bone mass or excessive bone loss during adulthood. Factures induced by osteoporosis are a great burden to society. Hip fractures are the most serious, as they nearly always result in hospitalization. According to the WHO fracture rates increase rapidly with age and the lifetime risk of fracture in 50 year-old women is about 40%, similar to that for coronary heart disease. In 1990, there were 1.7 million hip fractures alone worldwide; with changes in population demographics, this figure is expected to rise to 6 million by 2050.
Therefore there is an urgent need to provide factors effectively mediating bone angiogenesis and osteogenesis. The term “osteogenesis” or “ossification” as used herein refers to bone tissue formation. There are two types of ossification resulting in the formation of normal, healthy bone tissue. Intramembranous ossification is the direct laying down of bone into the primitive connective tissue (mesenchyme) occurring along a template of membrane. It results primarily in compact flat bones of the skull. During endochondral ossification mineral salts calcify along the scaffolding of cartilage used as a precursor. During embryogenesis the primary center of ossification, the diaphysis of the long bone is the first to form spongy bone tissue along the cartilage, followed by the epiphyses, which form the secondary centers of ossification and are separated from the diaphysis by a layer of uncalcified cartilage called the epiphyseal plate, where growth in bone length occurs. Compact bone tissue covering the bone's surface is produced by osteoblasts in the inner layer of the periosteum, producing growth in diameter. In fracture healing, endochondral osteogenesis is the most commonly occurring process.
It is the objective of the present invention to provide compounds or factors mediating bone angiogenesis and osteogenesis, which can be used as pharmaceutically active agents, especially for use in the treatment of osteoporosis or promotion of bone fracture healing.
The objective of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application.